Cover Page
The handle http://hdl.handle.net/1887/49402 holds various files of this Leiden University dissertation.
Author: Lenselink, E.B.
Title: Clavis Aurea? Structure-enabled approaches of identifying and optimizing GPCR ligands
Issue Date: 2017-06-07
Clavis Aurea?
Structure-enabled approaches of identifying and optimizing GPCR ligands
Eelke Bart Lenselink
The research described in this thesis was performed at the Division of Medicinal Chemistry of the Leiden Academic Centre for Drug Research, Leiden
University (Leiden, The Netherlands).
The research was financially supported by the Netherlands Organization for Scientific Research - Chemical Sciences (NWO-TOP #714.011.001).
Printed by Proefschriftmaken Cover design: Bart Lenselink
Thesis layout: Jettie Vernee and Bart Lenselink
© Bart Lenselink 2017 ISBN: 978-94-6295-671-1
All rights reserved. No part of this thesis may be reproduced in any form or by any means without the prior written permission
of the holder of copyright
Clavis Aurea?
Structure-enabled approaches of identifying and optimizing GPCR ligands
Proefschrift ter verkrijging van
de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof. mr. C.J.J.M. Stolker,
volgens besluit van het College voor Promoties te verdedigen op woensdag 7 Juni 2017
klokke 16.15 uur door
Eelke Bart Lenselink
geboren te 's-Gravenhage, Nederland
in 1988
Promotor: Prof. dr. A.P. IJzerman Prof. dr. H.W.T van Vlijmen
Promotiecommissie: Prof. dr. H. Irth (Chair, Leiden University)
Prof. dr. J.A. Bouwstra (Secretary, Leiden University) Prof. dr. Ir. G. E. M. Fraaije (Leiden University)
Prof. dr. P. Kolb (Philipps-Universität Marburg, Duitsland) dr. C. de Graaf (Vrije Universiteit Amsterdam, Nederland) Prof. dr. J.N. Kok (Leiden University)
About the title and cover pages
“Clavis aurea” literally means golden key in Latin. In literature it is often used in the con- text of finding a hidden meaning in text. Likewise in alchemy it is often associated with finding the recipe of transforming lead into gold. In drug discovery the key metaphor has many aspects, which are partly described throughout the thesis. Many keys (ligands) can open different locks (proteins) as shown on the (front) cover. Water molecules also play an important part in the opening of the lock (chapters 1,2 and 3). Interactions between the lock and the key can be described and used in multiple ways in 3d (chapter 5) and 2d (chapter 6). Moreover, free energy perturbation simulations are alchemical simulations which hopefully one day can aid the design of better (golden) keys (chapters 7 and chap- ter 8). Although we might have designed a perfect key, the question remains how this key might be beneficial for a given disease. With advances in other fields, such as systems biology, we might be able to peek through the lock, to see what is behind the door (how a key might work in a given disease). This is illustrated by the back cover where St. Peter’s dome is seen through the keyhole of a gate of the Villa del Priorato (based on a photo taken by Mariëtte Lenselink).
